Interior View
Improving today's prevention methods, EARLY DETECTION and knowledge about cervical cancer might rein in the number of cases.
The halcyon days and turbulent times of post-1940s America revolutionized the lives of women in more ways than even iconic wartime factory worker Rosie the Riveter would have envisioned.
As the doors of the workplace opened and the equal rights movement brought female voices into the national consciousness, women also achieved a momentous improvement in maintaining their health with the Papanicolaou smear.
Now usually called a Pap test, this routine screening-easily done in a doctor's office-has detected hundreds of thousands of abnormal cervical lesions in women before they could ever develop into cancer of the cervix. And with each case detected and treated early, women faced a far less frightening threat from this once-dreaded disease.
Although Pap smears have saved countless lives, the tests sometimes miss abnormal lesions and give false negatives, or show abnormal but inconclusive results. And women in many areas of the world do not have access to annual Pap tests or cannot afford them.
Globally, cervical cancer is the second or third most common cancer among women. In some developing countries, it remains the most frequent female cancer. More than 400,000 new cases are diagnosed each year, mostly among economically disadvantaged women-including those in the United States. About 200,000 women worldwide will die of it.For most American women, testing has certainly helped, physicians say. Incidence rates have declined by 40 percent over the last 30 years. Still, 13,000 Americans are expected to be diagnosed with cervical cancer this year; improving today's early detection and prevention methods and knowledge about this cancer might rein in the cases even further.
This cancer begins in the cervix, the area at the base of the narrow canal found at the bottom of the uterus. Hollow and shaped like an inverted pear, the uterus is located in a woman's lower abdomen, between the bladder and rectum. The cervical canal opens into the vagina, which leads to the outside of the body.
Physicians obtain samples of cells on the surface of the cervix by inserting an instrument through the vagina and swabbing, scraping or brushing the cervix. This is the Pap test, commonly done during routine pelvic exams.Cytopathologists examine the cells under a microscope, to detect any abnormal cells. Physicians then perform procedures to remove abnormal areas from the cervix before they become cancerous.
Unfortunately, some women may be getting false-negative results on these tests because aberrant tissue changes can keep abnormal cells from being picked up during the exam, according to a recent study led by Juan C. Felix, M.D., professor of clinical pathology and obstetrics and gynecology at the Keck School of Medicine.
Together with colleagues in California and Taiwan, Felix is the first to suggest this explanation for the frequent occurrence of false-negative Pap smears.
Nationwide, physicians perform about 55 million Pap tests every year. As many as four in 10 test results come back negative even when a biopsy shows abnormal lesions. Researchers have not been able to conclusively explain the inconsistencies.A substance called E-cadherin may lie at the heart of the problem, says Felix, whose research focuses on pathology and cytology-the study of cells-in women's cancers.
E-cadherin is a molecule that helps cells in the cervical tissue stick together, he says. Normally, E-cadherin can be found in cervical tissue, except on the cervix's surface: the superficial epithelial layers. With no E-cadherin there, older cells can detach and slough away from the surface of the cervix, much like dead cells are regularly exfoliated from the surface of the skin.
However, the researchers found that in some cervical lesions, E-cadherin was abnormally present in cells on the cervix's surface, keeping the abnormal epithelial cells anchored to the cells beneath them. Researchers theorize that if these abnormal cells can't be scraped or brushed off, they can't be examined under a microscope after conventional Pap testing.
"Never before have we seen such clear evidence that barriers to exfoliation are linked to false-negative Pap smears," he says.
The team conducted the study with tissue samples from 25 women known to have cervical dysplasia. Researchers analyzed whether the tissue samples showed normal distribution of E-cadherin, and then compared each sample to its corresponding Pap smear result. Of the 25 women with dysplasia, 12 had a normal Pap smear.All 12 of these women, however, had a positive result through speculoscopy with PapSure. PapSure is a new testing system that includes a special disposable light, or speculoscope, used during the pelvic examination, allowing physicians to actually see any suspicious lesions on the cervix. It is used alongside conventional Pap testing.
The remaining 13 women had abnormal Pap smears. Researchers were able to analyze E-cadherin distribution in 10 of these samples. Eight of 10 of these samples showed normal distribution of E-cadherin.
In contrast, of the 12 women with false- negative Pap smears, 10 of 11 samples that could be examined showed the abnormal presence of E-cadherin in the superficial layers of the cervix.
"Of the patients with known cervical abnormalities who had normal Pap smears, 91 percent had an abnormal distribution of the E-cadherin adhesion molecule," Felix says. He cautions, however, that larger studies with randomly selected patients are needed to verify the findings. Other adhesion molecules also may be involved in the process.
Possible alternative reasons for false-negative Pap smears include poor cell sample collection, mistakes in transferring cells to slides and human error in evaluating the collected cells, he adds.
Even with improved testing technology, invasive cervical cancer is likely to remain an issue for many women coming to the LAC+USC Medical Center, says Laila Muderspach, M.D., associate professor of obstetrics and gynecology at the Keck School of Medicine.
One of every 13 new cancers found at LAC+USC is cervical cancer she explains. The reason: The women often have never had a Pap test, or last had a Pap more than a decade ago.
So Muderspach and her colleagues are mounting an innovative campaign to battle cervical cancer in the form of a vaccine. Researchers at USC/Norris Compre-hensive Cancer Center and LAC+USC's Women's and Children's Hospital have launched clinical trials of two vaccines
for women who have been found to have precancerous lesions on the cervix.The goal behind the investigative vaccine technique is to harness the body's own immune system to halt cellular changes in the cervix, heal the lesions and keep them from becoming cancerous.
"If this works, then ideally when we find a patient who has the precursors of this cancer, we would be able to vaccinate her and reverse the abnormalities," says Lynda Roman, M.D., associate professor of obstetrics and gynecology at the Keck School of Medicine.The vaccine idea revolves around cervical cancer's links to human papillomaviruses, or HPVs.
More than 80 types of HPV can be transmitted through sexual contact, making HPV a common infection. A few of the types, known to be high-risk viruses, may lead to cancer. These
usually cause lesions of abnormal cells that are flat and nearly invisible.HPVs are now recognized as the major cause of cervical cancer, according to the National Cancer Institute (NCI). Researchers believe they might spur cancers of genital areas, as well as the soft palate, tongue and tonsils.
Scientists hope disarming the virus will suppress cervical cancer's development-or prevent it altogether. "Vaccines are about creating a way to stimulate the immune system to clear the virus," Muderspach says. Each of the two vaccines under investigation at USC targets a particular virus strain.
For the USC trials, physicians seek women who have had a recent Pap smear or biopsy indicating specific, suspicious cellular changes. Women will be evaluated to make sure their lesion is completely visible and appropriate for the study.Once they enroll, women will get an injection at regular intervals for up to six months, and physicians will closely monitor the cervical lesions to ensure women are not at risk. In previous studies with both vaccines, side effects were generally confined to mild skin reactions at the site of the injection.
After six months, the lesion area will be removed through a loop electrosurgical excision procedure, or LEEP, which is a standard treatment for precancerous cervical lesions. "If the vaccine works, it could completely eradicate the cellular changes and they may never return-but we still need to do a LEEP to make sure that all the altered cells are removed," Muderspach says.
The California Department of Health Services and the NCI are sponsoring the studies, done in collaboration with the University of California, Irvine.
Jeffrey S. Weber, M.D., Ph.D., associate professor of medicine, molecular microbiology and immunology at the Keck School of Medicine, says that researchers worldwide are investigating many vaccine approaches to fight HPV and cancer.One strategy calls for generating an antibody response, says Weber, who holds the Lucy and Berle Adams Chair in Cancer Research.
For example, to provoke an antibody response, a vaccine might consist of a protein that is associated with HPV. When the protein is injected, the body develops other specific proteins in the blood-antibodies-that help to inactivate HPV.Alternately, researchers can try to generate a T-cell response in the body. T-cells are white blood cells that grab foreign invaders and sweep them away. By introducing other specially tweaked immune cells into the body through a vaccine, researchers seek to rev up T-cells to battle HPV, or even the cancer itself.
Vaccines elsewhere are under study for different checkpoints in the disease cycle. Previous vaccine studies on women who already have full-fledged cervical cancer have not reversed the cancer, Weber says. But a different trial is testing whether a vaccine can successfully fight existing HPV infection before any signs of cellular changes show up in the cervix, and yet another is examining if a vaccine given ahead of time can protect women from HPV infection entirely.The idea of preventing HPV infection from the start becomes even more powerful when one considers the women around the world who, despite great medical strides in the past 60 years, have no access to tests. The longer women go without receiving Pap tests, the greater the chance that any cervical cancer present will be found at a later, more dangerous stage.
"Ideally, if you could vaccinate everyone, you could prevent
people from getting HPV," Muderspach says, "and that would go a long way to reducing the threat of cervical cancer."
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